Pergamon

0040-4039(95)00158-1

Tetrahedron Letters, Vol. 36, No. 11, pp. 1925-1928, 1995 Elsevier Science Ltd

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Highly Chemoselective and Stereoselective Conjugate Addition of Benzyl Copper Reagents to ~-Oxoketene Dithioacetals

Barun K. Mehta, Hiriyakkanavar Iia* and Hiriyakkanavar Junjappa*

Department of Chemistry, North-Eastern Hill University Shillong - 793 003 (Meghalaya), India

Abstract : Benzyl copper reagents derived by transmetallation between benzylmagnesium chloride and Cu(1) species are shown to undergo conjugate addition - elimination with acyclic and cyclic ¢t --oxoketene dithioacetais to afford the corresponding fl-benzyl vinylogous thiolesters in highly stereo- and chemoselective manner.

During the course of our cycloaromatization studies on a-oxoketene dithioacetals, we have shown that

benzyl Grignard reagent la unlike their allyl lb and propargyl Ic counterparts undergoes sequential 1,4-

and 1,2-addition with these substrates. Subsequent cyclization of the resulting carbinols with boron

trifluoride etherate yielded aromatic compounds with undesirable benzylic side chain 1". This problem

was later on circumvented by utilizing fl-oxodithioacetals to afford carbinols via exclusive 1,2-addition 2.

In continuation of these studies, we aimed to synthesize a series of f~-benzyl vinylogous thiolesters (as

potential precursors for naturally occurring lignans) by chemoselective conjugate addition of benzyl

copper reagents to ~,-oxoketene dithioacetais. Our literature survey revealed that despite extensive

studies on conjugate addition of various alkyl, aryl, vinyl and allyl cuprates to a~-unsaturated carbonyl

compounds 3, similar investigation on benzyl copper reagents is rather limited 4'5, probably due to thermal

instability of these reagents 4. Similarly, although Dieter 6 has carried out a detailed study of chemo- and

stereoselective conjugate addition of organocuprates derived from primary, secondary and tertiary alkyl

ligands on acyclic and cyclic oxoketene dithioacetals, the corresponding benzyl copper reagents were

not investigated by these workers. We herein report a successful conjugate transfer of single benzyl

group to a-oxoketene dithioacetals to afford the corresponding l~-benzyl vinylogous thiolesters in highly

stereo- and chemoselective manner.

The benzyl copper reagents were prepared by transmetallation between benzylmagnesium chloride and

various Cu(I) species 5. Oxoketene dithioacetal 1 underwent smooth conjugate addition with

BnCu(X)MgCI to afford vinylogous thiolester 2 in 67% yield with exclusive Z configuration 7. No trace

of the corresponding E stereoisomer, or the product arising by replacement of second thiomethyl group

(or 1,2-addition product) was observed in the reaction mixture. The stereochemistry of 2 was assigned

1925

1926

T a b l e : Conjuga t e Addit ion o f Benzyl Copper Reagent to a - O x o k e t e n e Di th ioaceta ls

Entry Substrate Reagent/conditions Product " Yidd (%)

SMe SMe R ~ ' ~ S M e R ~ C H z R I

H H 1 1 R = C6H 5 A, B 2 R = R I = C6H 5 67 ~, 87 b

2 3 R =2-Furyl A,B 4 R =2-Furyl ;R I =C6H 5 68 a,83 b

3 5 R = Me A,B 6 R = M e , R I = C6H 5 57 a,69 b

4 5 R = M e C 7 R = M e ; R | =2,5(MeO)2C6H 3 630

O SMe O SMe ~ S M e ~ C H 2 C 6 H s

5 8 A, B 9 62 a, 73 b

Me O SMe SMe ~ C H ~ R i

6 10 A,B 11 R I = C6H 5 60 a,82 b

7 10 C t2 R 1 = 2,5(MeO)2C6H 3 67 c

O SMe .j~ .~Me P h ~ s P h Ph / y ~'CH2Ph

H H 8 13 A 2 67=

O SMe O SMe Ph~L"SMe P h ~ : ~ H

Me Me 9 14 A 15 68 a

O H O H P h ~ S M e Ph ~"CH2CoH s

H H 10 16 A, B 17 68 ~, 84 b

O H O H ~ S M e ~ CH2C6Hs

11 18 A, B 19 82 I, 87 b

A : BnMgCl( leqv . ) / C u C i ( l e q v . ) / E t ~ O - T H F / -78°C ; B : BnMgCl( leqv . ) / CuCl ( leqv . ) / T M S C I ( l . 2eqv . ) / T M E D A ( I . l e q v . ) / E t20-THF / -78~C ; C : 2 ,5 (MeO)~s i t3CH2MgCl( l eqv . ) /CuCl ( l eqv .~ / F_,t20-THF [- 78°C. a : yield in reaction conditions A ; b : yield in reaction condit ions B ; c : yield in reaction condit ions C.

1927

on the basis of differential NOE experiment and by examining equilibrium isomeric ratio in the

presence of dilute HCI 6b's. Also, cyclization of 2 under Simmons-Smith reaction conditions afforded

thiopbene 20 which further supported the assigned stereochemistry 9. Improved yield of Z 2 (87%) was

obtained by reacting 1 with BnCuTMSCI-TMEDA reagent, while the other benzyl copper reagents

afforded Z 2 in moderate to poor yields t°. High stereo- and chemoselectivity was also observed in

the reaction of other acyclic3,5 and cyclic8,10 ketene dithioacetals with these reagents to afford only

Z stereoisomers of the vinylogous thiolesters 4,6,(entries 2,3) and 9, l I (entries 5,6) respectively in good

yieldsH(Table). Our attempts to isolate other E stereoisomer in these reactions were unsuccessful. The

vinylogous thiolesters I I afforded the thiophene 21 under Simmons-Smith reaction conditions thus

further supporting its assigned stereochemistry 9. Ketene dithioacetal 13 with different mercapto groups

underwent replacement of only thiophenyl group under these conditions to afford Z 2 exclusively in

67% yield (Table), while tetrasubstituted ketene dithioacetal 14 gave only the reduced product 15 t].

Benzyl copper reagent derived from 2,5-dimethoxybenzylmagnesium chloride also underwent a facile

conjugate addition and elimination with 5 and 10 to yield the corresponding Z vinylogous thiolesters

7 and 12 in good yields (entries 4,7,Table)". The methodology could also be extended to vinylogous

thiolesters 16 and 15 which gave the corresponding E t~-benzylenones 17 and 19 in good yields

(entries 10,11) II.

Zn/Cu/CH2I+ _ P h ~ s ~ 1 1 Zn/Cu/CH212 i~ C HzC6H s 2 EtzO/Z~ ~ CH,C6H s Et20/Z ~

20 21

In conclusion, we have demonstrated a facile conjugate transfer of highly reactive benzyl copper

reagents to cx-oxoketene dithioacetals in chemo- and stereoselective manner to afford novel 8-benzyl

vinylogous thiolesters. The method should provide ample opportunity for synthetic variation employing

organocopper reagents containing functionalized benzyl iigands. Unusually high stereoselectivity

observed in these reactions is noteworthy. It is pertinent to note that in most of the organocuprate

additions studied by Dieter and coworkers on these systems, a mixture of E/Z vinylogous thiolesters were always obtained with predominant E isomer 6. Further studies are in progress to define the factors

controlling stereoselectivity and to explore the synthetic utility of the newly synthesized l~-benzyl

vinylogous thiolesters.

Acknowledgements : BKM thanks CSIR, New Delhi for Senior Research Fellowship. Financial

assistance under CSIR research scheme is also acknowledged.

References and Notes

I.

2.

(a) Balu, M.P.;Singh, G.; Ila, H.; Junjappa, H. Tetrahedron Lett. 1986,27, 117; (b) Singh, G.;

Ila, H.; Junjappa, H. Tetrahedron Let t .1984,25, 5095 ; (c) Gupta, A.K.;IIa, H.; Junjappa, H.

Tetrahedron Lett. 1987, 28, 1459.

Rao, Ch.S.;Balu, M.P.;IIa, H.; Junjappa, H. Tetrahedron 1991,47, 3499.

1928

3.

4.

5.

6.

7.

8.

9.

10.

11.

For Review see :(a) Posner, G.H. Org. Reactions 1972,19, 1; (b) Normant, J.F.J. Organomet.

Chem. Lib. 1976,1,219; (c) Lipshutz, B.H. Synthesis 1987, 325. (a) Linderman, R.J.; Godfrey, A.; Home, K. Tetrahedron 1989,45,495; (b) Berk, S.C.;Yeh,

M.C.P. ;Jeong, N.; Knochel, P. Organometallics 1990,9(12), 3053.

Van Heerden, P.S.;Bezuidenhoudt B.C.B.;Steenkamp J.A.; Ferreira, D. Tetrahedron Lett .1992,

33, 2383.

(a) Dieter, R.K.; Fishpaugh, J.R.; Silks, L.A. Tetrahedron Lett. 1982,23, 3751; 0a) Dieter, R.K.;

Silks, L.A. III ; Fishpaugh, J.R.; Kastner, M.F.J. Am. Chem. Soc. 1985,107, 4679; (c) Dieter,

R.K.; Silks, L.A.J. Org. Chem. 1983,48, 2786.

Analytical and spectral data for2 : light yellow crystals (CHC13/hexane); m.p. 109-110"C; IR

(KBr)1638, 1540, 1248 cml; IH NMR (CDC13 ; 250 MHz) b 2.26 (3H, s, SCH3), 3.96 (2H, s,

CH2Ph), 6.94(1H, s, =CH), 7.23-7.44(8H, m, ArH), 7.84-7.88(2H, m, ArH); 13C NMR (CDCI3;

62.5 MHz) b 14.21(SCH3) , 42.50(CH2Ph), 118.03(=CH), 126.81,127.64, 128.22,128.67, 131.75

(ARCH), 136.89, 138.90, 163.47 (quart. C), 188.31 (CO); m/z 268 (M ÷, 33%), 221(11), 105(100).

Irradiation of benzylic methylene protons at b 3.98 displayed NOE enhancement (5.2%) of

olefinic proton signal at 6 7.03 (or vice-versa), while no intensity enhancement was observed for

SMe signal when olefinic proton signal (8 7.03) was irradiated. For equilibrium experiment, pure

2 was dissolved in CDCI 3 in a NMR tube to which a trace of 50% HCI was added. Isomerization

process was monitored by NMR spectra and after 24h, equilibrium mixture contained 60 : 40

ratio of E and Z isomers. The l~-benzylic methylene protons cis to benzoyl group in the E

isomer of 2 appeared downfield (6 4.33) relative to the corresponding absorption for the Z

isomer (6 3.98). The olefinic and SMe proton signals for E isomer were present at b 6.68 and

8 7.03 respectively. These patterns are consistent throughout for all Z stereoisomers examined

and provide a reliable guide for the assignment of olefinic geometry in all vinylogous thiolesters.

(a) Thomas A.; Singh, G.; Ila, H.; Junjappa, H. Tetrahedron Lett. 1989,30, 3093; (b) Bhat, L.N.;

Thomas, A. ;Ila, H.; Junjappa, H. Tetrahedron 1992,48, 10377; (c) Bhat, L. N. ;Ila, H.; Junjappa, H. Synthesis 1993,959. It was shown earlier that E f~-methylthiomethyleneacetophenone does not

cyclize under Simmons-Smith reaction conditions to give 3-phenylthiophene ; ref. 9b.

Reaction conditions and yields (%) of 2 : BnMgC1 (leqv.)/CuBr.Me2S (leqv.)/Et~O-THF/-78 °C,

56% ;BnMgC1 (leqv.)/CuBr.MezS (leqv.)/BF3.Et20 (leqv.)/Et20-THF /-78°C, 62% ; BnMgC1 (leqv.)/CuCl(leqv.)/TMSCl (1.2eqv.)/ HMPA (1.1eqv.)/ Et20-THF /-78°C, 63% ; BnMgCI

(leqv.)/CuC1 (leqv.)/THF/-78 °C, 45% ; BnMgCl(leqv.)/CuCl (leqv.)/Et20/-78 °C, 32% ;

BnMgC1 (leqv.)/CuBr (leqv.)/EtzO-THF/-78 °C, 47%. Structures of all the new compounds prepared were confirmed with the help of spectral and analytical data, while the stereochemical assignments of these products were made by differential NOE experiments and by examining equilibrium isomeric ratio.

(Received in UK 16 November 1994; revised 13 January 1995; accepted 20 January 1995)